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• W4387307191 abstract "LGMD2I/R9 is an autosomal recessive disorder caused by pathogenic variants in FKRP. Cardiac involvement occurs in up to 60% of LGMDR9 patients. Previous studies have shown gene replacement therapies functionally rescue dystrophic mice with Fkrp mutations. Despite development efforts, gene replacement therapies are currently not available to LGMDR9 patients. Our study explored FKRP dosage using a mouse model of LGMD2I/R9 harboring a homozygous mutation (p.Pro448Leu) in Fkrp. We systemically delivered the human FKRP gene using AAV9 to the 6-week-old P448L mice using muscle specific promoters, either tMCK or CK8e at a dose of 3.00E+14 vg/kg. CK8e-FKRP mice treated mice died within 2 weeks post-injection with males dying earlier than females. Echocardiography and H&E staining on heart showed evidence of myocarditis and dilated cardiomyopathy, including lower ejection fraction and cardiac output, higher left ventricular cavity size and mass, increased inflammatory infiltration, and necrosis. In contrast, histology on skeletal muscles and heart sections of tMCK-FKRP dosed mice showed ameliorated dystrophic pathology. qRT-PCR and western blots were performed to quantify FKRP expression. Both constructs showed high expression in skeletal muscles and heart at the mRNA level when compared to wild-type. At the protein level, both constructs expressed in skeletal muscles but only CK8e-FKRP was highly expressed in heart. We hypothesize the higher expression in CK8e treated mice is the underlying cause of cardiotoxicity leading to fatal myocarditis and dilated cardiomyopathy. Our results demonstrated that over-expression of FKRP gene in heart induced cardiotoxicity. Previous reports have shown FKRP over-expression to have a toxic effect but this is the first that we are aware to formally report and analyze fatal cardiotoxicity by FKRP over-expression. Our study emphasized that cardiac status in patients in LGMDR9 patients should be considered in the inclusion criteria. LGMD2I/R9 is an autosomal recessive disorder caused by pathogenic variants in FKRP. Cardiac involvement occurs in up to 60% of LGMDR9 patients. Previous studies have shown gene replacement therapies functionally rescue dystrophic mice with Fkrp mutations. Despite development efforts, gene replacement therapies are currently not available to LGMDR9 patients. Our study explored FKRP dosage using a mouse model of LGMD2I/R9 harboring a homozygous mutation (p.Pro448Leu) in Fkrp. We systemically delivered the human FKRP gene using AAV9 to the 6-week-old P448L mice using muscle specific promoters, either tMCK or CK8e at a dose of 3.00E+14 vg/kg. CK8e-FKRP mice treated mice died within 2 weeks post-injection with males dying earlier than females. Echocardiography and H&E staining on heart showed evidence of myocarditis and dilated cardiomyopathy, including lower ejection fraction and cardiac output, higher left ventricular cavity size and mass, increased inflammatory infiltration, and necrosis. In contrast, histology on skeletal muscles and heart sections of tMCK-FKRP dosed mice showed ameliorated dystrophic pathology. qRT-PCR and western blots were performed to quantify FKRP expression. Both constructs showed high expression in skeletal muscles and heart at the mRNA level when compared to wild-type. At the protein level, both constructs expressed in skeletal muscles but only CK8e-FKRP was highly expressed in heart. We hypothesize the higher expression in CK8e treated mice is the underlying cause of cardiotoxicity leading to fatal myocarditis and dilated cardiomyopathy. Our results demonstrated that over-expression of FKRP gene in heart induced cardiotoxicity. Previous reports have shown FKRP over-expression to have a toxic effect but this is the first that we are aware to formally report and analyze fatal cardiotoxicity by FKRP over-expression. Our study emphasized that cardiac status in patients in LGMDR9 patients should be considered in the inclusion criteria." @default.
• W4387307191 created "2023-10-04" @default.
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• W4387307191 date "2023-10-01" @default.
• W4387307191 modified "2023-10-05" @default.
• W4387307191 title "P299 Over-expression of FKRP in heart induces myocarditis and dilated cardiomyopathy in LGMD2I/R9 mice" @default.
• W4387307191 doi "https://doi.org/10.1016/j.nmd.2023.07.209" @default.
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